Bipolar Disorder
Conditions
Keywords
Mania
Brief summary
This study will evaluate the effectiveness of the medications, lithium (Eskalith®), valproate (Depakote®), and risperidone (Risperdal®) in treating children and adolescents with bipolar disorder or symptoms of mania.
Detailed description
Patients are randomly assigned to receive lithium (Eskalith), valproate (Depakote), or risperidone (Risperdal) for 8 to 16 weeks. They will have weekly visits to monitor their response to the medication. When the study is complete, care will be transferred to the child's treating psychiatrist.
Interventions
DRUGLithium carbonate
Titrated until blood level is 1.1 to 1.3 mEq/L
DRUGValproate
Titrated until blood level is 111 to 125 ug/mL
DRUGRisperidone
Titrated by weight until dose is 2.0 mg BID to 3.0 mg BID
Sponsors
National Institute of Mental Health (NIMH)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
* DSM-IV criteria for bipolar I (manic or mixed) or mania for at least 4 weeks * CGAS less than or equal to 60 * Good physical health
Exclusion criteria
* Schizophrenia or any pervasive developmental disorder * Major medical or neurological disease * History of addiction to illicit substances or alcohol or drug abuse within the last 4 weeks * IQ less than 70 * Pregnancy or breast-feeding * Unacceptable methods of contraception * In-patient care at baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impressions-Bipolar Mania Improvement | Measured at Week 8 | The Clinical Global Impressions-Bipolar (CGI-BP) assessment instrument measured improvement in mania, depression, and overall bipolar illness. The primary outcome measure was mania improvement, which measured the change in mania from baseline. Scores were 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Side Effects Form for Children and Adolescents | Measured at Week 8 | The Modified Side Effects Form for Children and Adolescents includes 62 potential side effects, with measures of frequency and severity for each item. Frequencies are 0=not present, 1=1-2 days, 2=3-4 days, 3=5-7 days. Severity scores are 0=not present, 1=mild (does not interfere with functioning), 2=moderate (some interference with functioning), 3=severe (functioning is significantly impaired because of side effects). Items for cardiovascular, gastrointestinal, central nervous system, ocular, mouth and nose, genito urinary, dermatology, musculo-skeletal, and other side effects are included. For analyses, side effects that were reported at any frequency and a severity of 2 or greater were considered present. |
| K-SADS Mania Rating Scale | Measured at Week 8 | The K-SADS Mania Rating Scale (KMRS) is comprised of 15 items modified from WASH-U-KSADS items. The individual items are scored on a 1-6 severity scale and then these item scores are summed to create an overall KMRS score. Guidelines for interpretation are as follows: 0-11 = no or minimal mania, 12-17 = mild mania, 18-25 = moderate mania, 26+ = marked or worse mania. The maximum possible score is 64. |
Countries
United States
Participant flow
Recruitment details
Recruitment was from media advertisements and clinical referrals from 2003 to 2008. There were a total of N=379 subjects randomized to 1 of the 3 group strata. The strata were (1) medication-naive strategy, (2) add-on strategy, and (3) cross-taper strategy. Analyses have only been conducted on the N=279 subjects in the first stratum.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Medication - Lithium Participants will receive treatment with lithium for 8 to 16 weeks. At the initial dispensing visit, dose was 150mg qHS for 2 days, then 150mg BID for subjects \<25kg; 150mg BID for 2 days, then 300mg BID for subjects 25-50kg; 300mg BID for 2 days, then 300mg AM / 600mg PM for subjects \>50kg. Dose was adjusted to achieve blood levels of 0.8 mEq/L at week 1, 0.9-1.0 mEq/L at weeks 2-3, and 1.1-1.3 mEq/L at weeks 4-7. | 137 |
| Randomized Medication - Divalproex Sodium Participants will receive treatment with divalproex sodium for 8 to 16 weeks. At the initial dispensing visit, dose was 125mg qHS for 2 days, then 125mg BID for subjects \<25kg; 250mg qHS for 2 days, then 125mg AM / 250mg PM for subjects 25-50kg; 250mg qHS for 2 days, then 250mg BID for subjects \>50kg. Dose was adjusted to achieve blood levels of 75 ug/ml at week 1, 100-110 ug/ml at weeks 2-3, and 111-125 ug/ml at weeks 4-7. | 139 |
| Randomized Medication - Risperidone Participants will receive treatment with risperidone for 8 to 16 weeks. At the initial dispensing visit, dose was 0.25mg qHS for 2 days, then 0.25mg BID for subjects \<25kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects 25-50kg; 0.25mg BID for 2 days, then 0.5mg BID for subjects \>50kg. Dose was adjusted at weeks 2-3 to 0.5mg BID for subjects \<25kg, 1.0mg BID for subjects 25-50kg and \>50kg. Dose was adjusted at weeks 4-5 to 1.0mg BID for subjects \<25kg, 1.5mg BID for subjects 25-50kg, 2.0kg BID for subjects \>50kg. Dose was adjusted at weeks 6-7 to 2.0mg BID for subjects \<25kg, 2.0mg AM / 3.0mg PM for subjects 25-50kg, 3.0mg BID for subjects \>50kg. | 103 |
| Total | 379 |
Baseline characteristics
| Characteristic | Randomized Medication - Divalproex Sodium | Randomized Medication - Risperidone | Randomized Medication - Lithium | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 139 Participants | 103 Participants | 137 Participants | 379 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 9.85 years STANDARD_DEVIATION 2.37 | 10.99 years STANDARD_DEVIATION 2.95 | 9.92 years STANDARD_DEVIATION 2.79 | 10.19 years STANDARD_DEVIATION 2.73 |
| Region of Enrollment United States | 139 participants | 103 participants | 137 participants | 379 participants |
| Sex: Female, Male Female | 70 Participants | 52 Participants | 53 Participants | 175 Participants |
| Sex: Female, Male Male | 69 Participants | 51 Participants | 84 Participants | 204 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 137 | 0 / 139 | 0 / 103 |
| serious Total, serious adverse events | 6 / 137 | 4 / 139 | 5 / 103 |
Outcome results
Primary
Clinical Global Impressions-Bipolar Mania Improvement
The Clinical Global Impressions-Bipolar (CGI-BP) assessment instrument measured improvement in mania, depression, and overall bipolar illness. The primary outcome measure was mania improvement, which measured the change in mania from baseline. Scores were 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.
Time frame: Measured at Week 8
Population: CGI-BP mania improvement data were analyzed for all subjects completing 8 weeks of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Medication - Lithium | Clinical Global Impressions-Bipolar Mania Improvement | 2.49 units on a scale | Standard Deviation 1.05 |
| Randomized Medication - Divalproex Sodium | Clinical Global Impressions-Bipolar Mania Improvement | 2.73 units on a scale | Standard Deviation 1.08 |
| Randomized Medication - Risperidone | Clinical Global Impressions-Bipolar Mania Improvement | 1.70 units on a scale | Standard Deviation 0.63 |
Secondary
K-SADS Mania Rating Scale
The K-SADS Mania Rating Scale (KMRS) is comprised of 15 items modified from WASH-U-KSADS items. The individual items are scored on a 1-6 severity scale and then these item scores are summed to create an overall KMRS score. Guidelines for interpretation are as follows: 0-11 = no or minimal mania, 12-17 = mild mania, 18-25 = moderate mania, 26+ = marked or worse mania. The maximum possible score is 64.
Time frame: Measured at Week 8
Population: KMRS data were analyzed for all subjects completing 8 weeks of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Medication - Lithium | K-SADS Mania Rating Scale | 24.06 units on a scale | Standard Deviation 12.11 |
| Randomized Medication - Divalproex Sodium | K-SADS Mania Rating Scale | 26.31 units on a scale | Standard Deviation 11.71 |
| Randomized Medication - Risperidone | K-SADS Mania Rating Scale | 14.58 units on a scale | Standard Deviation 7.47 |
Secondary
Modified Side Effects Form for Children and Adolescents
The Modified Side Effects Form for Children and Adolescents includes 62 potential side effects, with measures of frequency and severity for each item. Frequencies are 0=not present, 1=1-2 days, 2=3-4 days, 3=5-7 days. Severity scores are 0=not present, 1=mild (does not interfere with functioning), 2=moderate (some interference with functioning), 3=severe (functioning is significantly impaired because of side effects). Items for cardiovascular, gastrointestinal, central nervous system, ocular, mouth and nose, genito urinary, dermatology, musculo-skeletal, and other side effects are included. For analyses, side effects that were reported at any frequency and a severity of 2 or greater were considered present.
Time frame: Measured at Week 8
Population: Modified Side Effects Form for Children and Adolescents data were analyzed for all subjects completing 8 weeks of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Medication - Lithium | Modified Side Effects Form for Children and Adolescents | 5.11 side effects at week 8 | Standard Deviation 3.54 |
| Randomized Medication - Divalproex Sodium | Modified Side Effects Form for Children and Adolescents | 4.95 side effects at week 8 | Standard Deviation 3.29 |
| Randomized Medication - Risperidone | Modified Side Effects Form for Children and Adolescents | 3.70 side effects at week 8 | Standard Deviation 2.42 |